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Summary

Epidemiology

The syndrome is extremely rare. Fourteen cases born into consanguineous families, from the Middle East, India and Spain have been reported.

Clinical description

Onset is generally within the first two years of life although it may present later in childhood (range 1 month to 8 years) as bone pain. Chronic recurrent multifocal osteomyelitis (CRMO) associated with Majeed syndrome is typically more severe than that of non-syndromic CRMO, and is more persistent, with short remissions and more frequent exacerbations. It can be associated with fever, joint pain, delayed bone age, growth failure, short adult stature, and development of flexion contractures. Patients also have a hypochromic, microcytic anemia with dyserythropoiesis present on 11 of 11 bone marrow biopsies. In half of the cases, the anemia is mild with the remainder requiring one or more transfusions for anemia. The inflammatory neutrophilic dermatosis Sweet syndrome has been reported in two patients with Majeed syndrome. Other reported manifestations include failure to thrive, hepatomegaly, neutropenia, and transient cholestatic jaundice. The course is chronic and the syndrome may have a significant impact on quality of life.

Etiology

Majeed syndrome is caused by a mutation in LPIN2 (18p11.31), which encodes phosphatidate phosphatase LPIN2 (Lipin-2), important in lipid metabolism. Recent studies have shown that Lipin-2 is a negative regulator of the NLRP3 inflammasome.

Diagnostic methods

The diagnosis is based on the typical clinical manifestations and on molecular genetic testing of the causative gene mutation. Osteomyelitis can be diagnosed on skeletal radiographs but may require magnetic resonance imaging (MRI). Bone, bone marrow and skin biopsies may also be needed.

Differential diagnosis

Antenatal diagnosis

Prenatal diagnosis is possible in affected families when a disease causing mutation has been identified.

Genetic counseling

Majeed syndrome follows an autosomal recessive pattern of inheritance. Genetic counseling can inform parents with an affected child of their 25 % chance of having an affected child with each pregnancy.

Management and treatment

Treatment is empiric. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the main treatment options for non-syndromic CRMO, but are not likely to control bone inflammation in Majeed syndrome patients. Corticosteroids may also be used to control CRMO and inflammatory dermatosis, but have a multitude of side effects that limit their use for long term treatment. Methotrexate with or without pamidronate has been utilized in a few cases with mild to moderate improvement reported. TNF inhibitors were used in 2 children without significant benefit. IL-1 beta inhibition looks more promising with resolution of clinical symptoms, normalization of blood inflammatory markers and normalization of radiologic bone lesions in 4 of 4 patients treated.

Prognosis

The prognosis has generally been poor because of progressive bone and hematological manifestations, however, outcomes have improved with more aggressive treatments. There is limited information on long-term outcomes in patients treated with IL-1 beta inhibitors but short-term follow-up has shown sustained clinical response to this biologic class.

Research activities on this disease

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